4-hydroxypregnenes



United States Patent 4-HYDROXYPREGNENES Frank B. Colton, Chicago, Ill., assignor to G. D. Searle & Co., Chicago, 111., a corporation of Illinois No Drawing. Application December 12, 1955 Serial No. 552,274

8 Claims. (Cl. 260-'397.45)

- The present invention relates to a new group of steroids and, specifically, to 4,21-dihydroxypregnene-3,ZO-diones, their ll-oxygenatecl and 17-oxygenated derivatives, and esters thereof. The compounds which constitute this invention can be represented by the general structural formulas wherein R and R are members of the class consisting of hydrogen and acyl radicals of lower hydrocarbon carboxylic acids, Y is a member of the class consisting of hydrogen and hydroxyl, and Z is a member of the class consisting of methylene (CH carbinol (CHOH), and carbonyl (CO) groups. The terms R and R can represent hydrogen and such acyl radicals as formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl and octanoyl, and branched-chain isomers thereof, said acyl radicals being lower alkanoyl radicals derived from alkanoic acids having fewer than 9 carbon atoms. R and R can also represent cyclic acyl radicals such asv cyclopentanepropionyl, cyclohexaneacetyl, benzoyl and toluyl.

' Suitable starting materials for the manufacture of the compounds of this invention are described in my copending applications Serial No. 440,269, now U. S. Patent No. 2,782,213, filed ,Iune-29,--.1-954, and Serial. No. 451,313,

now U. S. Patent No. 2,727,912, filed August 20,1954,

of which applications this isa continuation-impart.

.The compounds of thisinvention are, conveniently prepared by. subjecting a,4-aeyloxy-S-hydroxyjaregnane derivative or a 4,5-dihydr0xypregnane derivative to the,

' .70 reagent and reactionconditi'ons employed, introduction action'of a dehydratingagent- Depending on the specific of the double bond into either the 4,5- or the 5,6 position 2,829,150 Patented Apr. 1,

can be favored; For example, heating a 4-acyloxy-5- hydroxypregnane derivative corresponding to the general structural formula O-Acyl with p-toluenesulfonic acid in glacial acetic acid or with a mixture of a lower alkanol and a mineral acid, representatively methanol and concentrated hydrochloric acid, results in the formation of a reaction product having a 4,5-double bond. The product formed in this reactionis principally the 4-hydroxy derivative corresponding to the general structural formula The same product is obtained by treatment of a 4,5-dihydroxypregnane derivative under identical conditions.

When a 4-acyloxy-5-hydroxypregnane derivative of the class employed as starting materials for the manufacture of the compounds of this invention is dehydrated with thionyl chloride and anhydrous pyridine at about 0 C., entry of the double bond into the 5,6-position is facilitated, and the principal product is a 4-acyloxy-5-pregnene This method of dehydration is especially recommended for those compounds, such as llfi-hydroxy and 17-hydroxy derivatives, which can readily undergo other dehydration reactions under more vigorous conditions. Treatment of a S-pregnene derivative of this type in acetic acid solution with hydrochloric acid at room temperature for 5-30 minutes results in isomerization to the corre- In all of these struc tural formulas R, Y, and Z are defined as hereinbefore.

sponding 4-pregnene derivative.

Application ofthe thionyl chloride dehydration pro" cedure to a 4,5-dihydroxypregnane derivative yields the 4-hydroxy-5-pregnene, which is isomerized to the 4-h'y vdroxy-4-pregnene by treatment with mineral acid.

Preferred starting materials for use in the processes of this invention include the following polyhydroxy compounds and their 4,21-di-(lower)alkanoates: 4,5,21-trihydroxypregnane 3,20 dione, 4,5,1lfi,21 tetrahydroxypregnane 3,20 dione, 4,5,17u,21 tetrahydroxypregnane 3,20 dione, 4,5,l1fi,17a,21 pentahydroxypregnane 3,20 dione, 4,5,21 trihydroxypregnane- 3,11,20 trione, and 4,5,17oc,2l tetrahydroxypregnane- 3 ,1 1,20-trione.

Treatment of the esters of this invention with a hydrolysis medium such as refluxing aqueous methanol and hydrochloric acid yields polyhydroxy compounds of the general formula CHIOH When a 4,21-dihydroxy derivative, a 4,115,21-trihydroxy derivative, a 4,l7a,2l-trihydroxy derivative, or a 4,115, 17,2l tetrahydroxy derivative corresponding to this structural formula is subjected to reaction with an acylating agent such as a lower alkanoic acid anhydride in pyridine solution, esterification occurs preferentially with hydroxyl groups at the 4- and 21-positions. If an 1104- hydroxyl group is substituted for an llfi-hydroxyl group, esterification at this position is facilitated.

The compounds of the present invention have valuable pharmacological properties. Specifically, they are potent hypotensive agents. They also exhibit selective hormonal and anti-hormonal properties, being, for example, elfective in inhibiting the sodium retention caused by desoxycorticosterone and its esters.

This invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only and it will be. understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein, as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples temperatures are given in degrees centigrade C.) and quantities of materials in parts by weight.

Example 1 To a solution of 2 parts of 4,2l-diacetoxy-S-hydroxypreguane-3,20-dione in 210 parts of glacial acetic acid is added 1 part of ptoluenesulfonic acid, and the reaction mixture is heated for 19 hours at 70 C. Then ice is added and the precipitate is collected on a filter, washed with water and taken up in-ethyl acetate. After charcoal decolorization the ethyl acetate solution is evaporated and the residue is treated with low boiling petroleum ether. Recrystallized from aqueous methanol, the 4-hydroxyll desoxycorticosterone acetate (4-hydroxy 21 acetoxy 4 pregnene-3,20-dione) obtained melts at about 24l-242 C. The ultraviolet absorption spectrum shows a maximum at 278 millimicrons with a molecular extinction coefficient of 12,300.

Example 2 A stirred suspension of 1 part of 4,2l-diacetoxy-5- hydroxypregnane-3,20-dione, 6.3 parts of methanol and 18 parts of concentrated hydrochloric acid is heated under reflux for 5 minutes. The reaction mixture is diluted with a total of 40 parts of water added in small portions, and is then cooled to about 0 C. The precipitated product is collected on a filter and washed with water. Purification by repeated recrystallization 4 from methanol affords 4,2l-dihydroxy-4-pregnene-3,20- dione melting at about 210-2l4 C. This compound has the structural formula CHaOH Example 3 A reaction mixture prepared from 1 part of 4,21- dihydroxy4-pregnene-3,20-dione, 4 parts of pyridine and 4 parts of acetic anhydride is allowed to stand, with occasional shaking, for 90 minutes at about 25 C. The mixture is diluted with ice water, and when precipitation of the product is complete, it is collected on a filter and washed with water. Purification by recrystallization from aqueous methanol and then from a mixture of ethyl acetate and petroleum ether yields 4,2l-diacetoxy- 4-pregnene-3,20-dione finally melting at about 197-199 C. after prior fusion and resolidification at about 180 C. This compound has a specific rotation of +l68 in chloroform solution and an ultraviolet absorption maximum at 245.5 millimicrons with a molecular extinction cocfiicient of 15,900.

Example 4 Concentrated hydrochloric acid (60 parts) is added to a solution of 3 parts of 4,2l-diacetoxy-5-hydroxypregnane-3,20-dione in 20 parts of warm methanol, and the reaction mixture is heated under reflux for 8 minutes. It is gradually diluted with several times its volume of hot water, and then cooled to about 0 C. The precipitated product is collected on a filter, washed with water and dried. A solution of this crude product, 8 parts of pyridine and 8 parts of acetic anhydride is allowed to stand at about 25 C. for 4 hours. Ice water is added, and when precipitation of the product is complete, it is collected on a filter and washed with water. Purification by recrystallization from mixtures of ethyl acetate and cyclohexane or from mixtures of ethyl acetate and petroleum ether affords 4,2l-diacetoxy-4-pregnene-3,20-dione, identical with the product of Example 3.

Example 5 A reaction mixture prepared from 2.5 parts of 4,21- dihydroxy-4-pregnene-3,20-dione, 12 parts of pyridine and 10 parts of propionic anhydride is allowed to stand for 20 hours at about 25 C. The mixture is diluted with ice water and maintained at about 0-10 C. for an additional 4 hours. The precipitated product is then collected on a filter and washed with water. This product is 4,21 -dipropionoxy-4-pregnene-3,20-dione.

Example 6 By the procedure of Example 5, with the substitution of 4-hydroxy-'21-acetoxy-4-pregnene-3,20-dione for the 4,21-dihydroxy-4-pregnene-3,20-dione, there is obtained 4-propionoxy-21-acetoxy-4-pregnene-3,20-dione.

Example 7 Example 9 To a solution of 23 parts of 4,21-diacetoxy-5-hydroxypregnane-3,20-dione in 300 parts of anhydrous pyridine is gradually added a total of 82 parts of thionyl chloride. The reaction mixture is maintained at C. for an additional6 minutes, and is then poured into a solution of sodium bicarbonate in ice water. This mixture is extracted with ethyl acetate. The organic phase is washed with dilute hydrochloric acid and with several portions of water, dried, and concentrated under reduced pressure. The residue is recrystallized from a mixture of ethyl acetate and cyclohexane and then from a mixture of acetone and petroleum ether to yield 4,21-diacetoxy-- pregnene-3,20-dione containing only a small amount of the A isomer and melting at about 171-174 C. It shows little selective absorption in the ultraviolet at 245 millimicrons. A sample placed on a preheated block exhibits the irregularities in melting point characteristic of a solvated material. This compound has the structural formula V OHa CHrOG OCH:

CHaC O Example A solution of 10 parts of 4,21-diacetoxy-5,17u-dihydroxypregnane-3,11,20-trione in 200 parts of anhydrous pyridine is cooled to about 0 C. and treated by the gradual addition of 40 parts of thionyl chloride. The reaction .mixture is maintained at about 0 C. for 5 minutes and uene-3,20-dione. U

sorption in the ultraviolet at about-245 millimicrons with Example 11 A solution of 12.5 parts of 4,2l-diacetoxy-lh-hydroxy- 5-pregnene-3,l1,20-trione, 160 parts of acetic acid and 18 parts of concentrated hydrochloric acid is allowed to stand for 5 minutes at about 25 C. Ice Water is then added, and when precipitation of the product is complete it is collected on a filter and washed with water. Successive crystallizations from aqueous acetone, from a mixture of ethyl acetate and petroleum ether, from a mixture of ethyl acetate and cyclohexane, and again from aqueous acetone afiord 4,21-diacetoxy-l7a-hydroxy-4- pregnene-3,11,20-trione melting at about 23l-233 C.

This compound has the structural formula A solution of 3 parts of 4,2l-diacetoxy-5,115,170:- trihydroxypregnane-3,20-dione in parts of anhydrous pyridine is cooled to about 0 C. and treated by the addition, in small portions, of a total of 20 parts of thionyl chloride. The reaction mixture is maintained at about 0 C. for 5 minutes and then poured into aqueous sodium bicarbonate. This mixture is rapidly extracted with ethyl acetate, and the organic phase is washed with dilute hydrochloric acid and with several portions of water. It is then dried and concentrated in a nitrogen atmosphere. Purification of the residue by repeated crystallizationfrom mixtures of ethyl acetate and cyclohexane or by .chromatography on a silica gel columnafiords a product which has little selective absorption in the ultraviolet and is substantially 4,21 diacetoxy-l1 8,17a-dihydroxy-5-pregnene- 3,20-dione, containing only a small amount of the A isomer. The structural formula is ([lHiOC OCH:

Example 13 Q A solution of 4p ar ts of 4,21-diacetoxy-11B,l7a-dihydroxy-5-pregnene-3,20-dione, parts of acetic acid and 12 parts of concentrated hydrochloric acid is allowed to stand for 5 minutes at about 25 C. Ice water is then added, and when preciptation of the product is complete it is collected on a filter and washed with water. Purification by successive crystallization from aqueous methanol and from a mixture of ethyl acetate and petroleum ether affords 4,21-diacetoxy-l1fl,17u-dihydroxy-4-preg- This compound exhibits selective abspam-so "7 a molecular extinction coeflicientof about 12,500. structural formula is The CEO OCH:

Example 14 By the procedure of Example 12, with the substitution of 4,21 diacetoxy-S,17a-dihydroxypregnane-3,20-dione for the 4,21-diacetoxy-5,1 1 [3,17 a-trihydroxypregnane-3 ,20- dione, there is obtained a product which is substantially 4,21-diacetoxy-17a-hydroxy-5-pregnene-3,20-dione of the structural formula CHzOG 00131! CHaCO Example One part of 4,21-diacetoxy-115,17a-dihydroxy-4-pregnene-3,20-dione is dissolved in 40 parts of methanol. Water (10 parts) and concentrated hydrochloric acid (2 parts) are added and the reaction mixture is heated under reflux for 30 minutes. The cooled reaction mixture is diluted with water and refrigerated until separation of the product is complete. The precipitated product is collected on a filter and purified by repeated recrystallization from aqueous methanol and from a mixture of ethyl acetate and cyclohexane. This compound is 4,11}3,17a,21- tetrahydroxy-4-pregnene-3,20-dione which has an ultraviolet absorption maximum at about 278 millimicrons with a molecular extinction coefficient of about 12,300. The structural formula is What is claimed is: I 1 1. A member of the class consisting of compounds pounds of thestructural formulas and ClHzo R C O CHZt/\ L--.Y Z Q wherein R and R are members of the class consisting of hydrogen and lower alkanoyl radicals, Y is a member of the class consisting of hydrogen and hydroxyl, and Z is a member of the class consisting of methylene, carbinol, and carbonyl groups.

2. A compound of the structural formula -(lower)aiknnoyl 3. 4, 2l-diacctoxy-4-pregnene-3,20-dione. 4. A compound of the structural formula 5. 4,21 diacetoxy 17oz hydroxy 4 pregnene- 3,11,20-trione.

6. A compound of the structural formula -(lower)alkanoyl 10 7. 4,21 diacetoxy 115,170; dihydroxy 4 -p1'egnene- 3,20-dione.

8. 4,11fl,17a,21 tetrahydroxy 4 pregnene 3,20- dione. I 6

References Cited in the file of this patent I UNITED STATES PATENTS 2,671,096 Murray Mar. 2, 1954 

1. A MEMBER OF THE CLASS CONSISTING OF COMPOUNDS POUNDS OF THE STURCTURAL FORMULAS 